Quaternary ammonium salts of 2, 6-lupetidine



Patented Mar. 25, 1952 I UNITED STATES PATENT OFFICE QUATERNARY AMMONIUM SALTS OF 2,6-LUPETIDINE RichardA. Robinson, Morton Grove, Ill.,assignor 'toG..D. Seai'le.l& 00., Skokie, 111., a. corporation'of Illinois NoDraWing. Application March 10, 1948, Serial No. 14,164

4'Claims. (Cl. 260293) 1 p z This invention relates to quaternary ammo- My invention is further disclosed by the follownium salts derived from 2,6-lupetidine,. and to ing'compounds,whichareztypicarofthosefiwithin the preparation thereof. More particularly, it the purview of this application.

relatesto substances having'the general-strum A. 1-methyl-1-ethy1-2,6-lupetidinium bromide, tural formula 5 which has the formula I OH; OH;

R i CHs I 0m "N-C H \cfifid \X om-o Bi 5 H3 (EH3 wherein R and R are alkyl, alkenyLaralkyl, or B. slupfldmmm tchlm hydroxyalkyl radicals having a total-number of ride, of the formula carbon atoms of 3 to 10, and X represents a monovalent anion, preferably a halide ion. CH3

'The compounds which comprise this invention H CH3 are useful surface-active substances. They are also in general antiseptics andgermicides. The H compounds are of valueas .antispasmodic and 0112-0 01 antihistaminic agents and as autonomic gang- Home blocking agents. It is the object of this invention to provide .newcompositions of matg' g 1;$; etldm'mm i havmg ter which are of value for the foregoing uses. It OH is a further object of this invention to provide 3 effective methods for producing such-substances. CHP-UH s In the compounds of the foregoing general C +0211, structural formula, R -and R' can represent alg kyl-radicalssuchas methyl, ethyl, propyl, iso- T- H r propyl, butyl, isobutylamyl, hexyl, heptyl, voctyl, nonyl, and the like, wherein the alkyL-radical D. l-n-propyl 1 'y -'hydroxypropy1-2,6- may have a straight or branched chain. ,Rand lupetidinium chloride, whichhas the formula R further represent hydroxyalkylradicalsderived from the foregoing alkylene radicals by theintroduction of one ormore hydroxyl groups. 2'- OH2O2H5 In particular they represent hydroxyalkyl radi- N CH2CH2OH20H cals such as fi-hydroxyethyl, fi-hydroxypropyl,

'y hydroxypropyl, fl/Y dihydroxypropyl, -B-hydroxybutyl, fi-hydroxy-butyl, and the like. R and H3 R can also stand for alkenyl radicals, as for 40 bmmomllmethm 2,6 dulletidinium; example, allyl, methallyl, :crotyl and the like. aide, of the formula One of thejgroups Rand R can be an ara'lkyl CH3 radical such as benzyl or phenethyl, the total number of carbon atoms of R and R being 3 to 10. H CH3 "In the foregoing formula, Rand R may repre- 0 2 N-CH2 2H fi se'nt'th'e same radical or they may represent cfi' I widelyfiifierentradicals, as for example, ethyl g and'phenethyl.

The anion X is chosen from inorganic and or- 1-fl-hydroxyethy1-1-methy1 2 6 1upetidinium ganic ions such as chloride, iodide, bromide, bromidehaving the formula acetate, benzoate, benzenesulfonate, p-toluenesulfonate; o-toluenesulfonate,methosulfate, etho- CH3 su1fatepand7thelike. It further represents or- CH H ganic anions such as those 'derivedfrom the "haloxanthinesas for exam'ple;Bathlorotheophyllin, -8-brornotheophy1lin, 8 ch10rocaffeine,:and the CHPC 1 Br dike.

. 3 G. l-butyl-1-isobutyl-2,6-lupetidinium bromide of the formula H. l-fi-acetoxyethyl-1-methyl-2,6-lupetidinium bromide, of the formula I. 1,1-bls ,8 hydroxyethyl 2,6 -1upetldinium chloride, having the formula CH3 CHz-( JH CHzCHzOH CH, N-CHzCHzOH CHzC 01 J. l-benzyl-1-;3-hydroxyethyl-2,6-lupetidinium chloride, of the formula HzCHuOH N 2 sHs L. l-allyl-l-isopropyl 2,6 lupetidinium bromide, which has the formula M. 1-methyl 1 1 .7 dihydroxypropyl-2,6- lupetidinium chloride, of the formula CHz- H CH;

CH: N-CHzOHOHCHiOH CHg-C C] N. l-nonyl-l-methyl 2,6 lupetidinium iodide, of the formula The compounds of this invention are prepared by treating a 1-alkylor l-alkenylor l-hydroxyalkyl-2,6-lupetidine of the following formula wherein R is an alkyl, alkenyl or hydroxyalkyl group, with an alkyl or alkenyl or hydroxyalkyl or aralkyl halide in the presence or absence of an inert solvent. While it is generally preferable to use a solvent in which the reagents are soluble and the quaternary ammonium salt is insoluble, this is not essential. Among such solvents are acetone, methyl ethyl ketone, aliphatic ethers, petroleum hydrocarbons, benzene, toluene, polyhalogenated hydrocarbons, and the like. Nitroparaffins such as nitromethane and nitroethane are excellent media for the reactions. These substances are solvents for the salts as Well as the bases and must be evaporated. They appear to catalyze the reaction and are for this reason desirable. The quaternary ammonium salts may also be produced by treating a l-substituted-2,6- lupetidine of the foregoing type with an alkyl sulfate or an alkyl arylsulfonate in the presence or absence of a solvent.

In general the desired quaternary ammonium salts crystallize upon chilling, and may be readily separated from the reaction mixtures. They may be purified by recrystallization or by washing with a suitable solvent. These compounds are soluble in water, being salts of strong bases with strong acids. They are frequently soluble in organic solvents such as alcohols. It is often possible to convert one quaternary ammonium salt of the type to Which this application relates to a quaternary ammonium salt of another acid. For example, a quaternary ammonium iodide may be converted to the corresponding chloride by reacting the iodide with silver chloride in Water and alcohol, or other lower organic solvent. In a similar way, a halide may be substituted by a more complex organic anion such as a benzoate, an acetate, or an 8-haloxanthine ion, by the use of a heavy metal salt of the complex organic anion.

My invention is further illustrated by the following examples, which are presented for the purpose of illustration and which are not intended to limit the invention in spirit or in scope. The relative amounts of materials are given in parts by weight.

Example 1 40 parts of 1-methyl-2,6-lupetidine and 40 parts of ethyl bromide are dissolved in 60 parts of methyl ethyl ketone and heated in a closed vessel for 2 hours at 100 centigrade. The reaction mixture is chilled and the crystalline precipitate of l-methyl-1-ethyl-2,6-lupetidinium bromide (Compound A) is removed by filtration and dried. After recrystallization from isopropanol, this quaternary salt melts at about 281 C.

Example 2 51 parts of 2,6-lupetidine and 25 parts of ethyl bromide in parts of methyl ethyl ketone are heated in a closed vessel for about 15 hours at 50-60 C. The precipitate of lupetidine hydrobromide is removed by filtration. The filtrate is evaporated and distilled. A mixture of secondary and tertiary amines boiling at 140-170 C. is obtained. This is treated with acetic anhydride, and then with p-toluene-sulfonyl chloride to remove secondary amine. The purified l-ethyl- 2,6-lupetidine distils at 163-167 C.

24 parts of 1-ethyl-2,6,-lupetidine, 20 parts of ethyl bromide, and 80 parts of methyl ethyl ketone are heated in a closed vessel for about 3 hours at 150-155" C. The reaction mixture is then chilled and the precipitate of 1,1-diethyl- 2,6-lupetidinium bromide (Compound C) is removed by filtration and washed with warm methyl ethyl ketone. After recrystallization from isopropanol, this quaternary salt melts at 263265 C.

Example 3 1-n-propyl-2,6-lupetidine is prepared by heating under pressure at 50-60" C. 23 parts of 2,6- lupetidine and 17 parts of n-propyl iodide. The precipitate of lupetidine hydriodide is removed by filtration, and the filtrate is evaporated. The residue of 1-n-propyl-2,6-lupetidine distills at about 104 C. at 65 millimeters pressure.

80 parts of 1-n-propyl-2,6-lupetidine and 100 parts of methyl iodide dissolved in 320 parts of methyl ethyl ketone are heated at about 50 C. in a closed vessel. An immediate reaction ensues and a precipitate of 1-n-propyl-1-methyl-2,6- lupetidinium iodide (Compound E) forms. This salt is removed by filtration, washed with methyl ethyl ketone, and melts at about 238 C. with decomposition.

Example 4 A solution of 108 parts of 1-ethyl-2,6-lupetidine, 193 parts of ethyl iodide and 85 parts of nitromethane is refluxed for 5 hours. The solvent is removed by evaporation under reduced pressure. The residue of 1,1-diethyl-2,6-lupetidinium iodide is collected ona filter and washed with methyl ethyl ketone. After drying at 50 residue of 1,1-diethy1-2,6-1upetidinium bromide is purified by recrystallization from isopropanol and melts at about 260 C.

I claim:

1. A new composition of matter having the following structural formula wherein R and R are members of the group consistingof alkyl and alkenyl radicals, and X is a monovalent anion, and wherein the total number of carbon atoms of R and R is at least 3 and not greater than 10.

2. A 1,1-dia1kyl-2,6-lupetidinium halide, wherein the total number. of carbon atoms of the alkyl radicals is at least 3 and not greater than 10.

3. 1,1-diethyl-2,6-lupetidinium bromide.

4. 1-methyl-1-ethy1-2,6-lupetidinium bromide.

RICHARD A. ROBINSON.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Chemical Abstracts (Kamizyo), vol. 34, p. 7428 (1940).

Mannich, Chem. Abstracts, vol. 28 (1934), pp. 4059-4061.

McElvain et al., J. Amer. Chem. Soc., vol. 681 (1946), pp. 2592-2600. 

1. A NEW COMPOSITION OF MATTER HAVING THE FOLLOWING STRUCTURAL FORMULA 